DK173556B1 - Polyol esters, their preparation and pharmaceutical use - Google Patents

Description

DK 173556 B1

The present invention relates to a novel ester of a polyol which is characterized by the characterizing part of claim 1. The invention also relates to a reaction product as claimed in claim 2, embodiments thereof being given in claims 3-5. The invention further relates to a method for producing a product 5 according to claim 1, which is characterized by the characterizing part of claim 6. The invention further relates to depot matrix materials as claimed in claims 7 and 8 and a parenteral pharmaceutical depot preparation for use as implant or microcapsules as claimed in claims 9 and 10.

A broad class of polyol esters with polymeric hydroxycarboxylic ester residues is disclosed in DE patent specification 1,020,034, in which glycerol esters having polylactide ester residues of 30 lactic acid residues or pentaerythritol esters having polylactic acid residues of 16 lactic acid residues are specifically described. The patent does not specifically describe longer chain polymer esters of polyols having at least 3 hydroxy groups.

15

These products are used as solvents, for example, for pharmaceutical purposes, as emulsifiers or as additives for synthetic and plastic materials. There is no description of their use in pharmaceutical matrix compositions.

20 *

Esters of sugar alcohols, for example, from erythritol, xylitol, ribitol and sorbitol, with poly-s-hydroxycaproic acid are described in Journal of Polymer Science, Polymer Chemistry Edition, 20, 1982, pp. 319-326, especially pp. 323-326.

The molecular weight of these esters depends on the degree of esterification of the hydroxy groups in the polyol esters and the length of the poly-e-hydroxy-capric acid residues. The order of magnitude is from approx. 26,000 to 65,000.

The esters have star polymer structure, with their single polyol residue as the central portion being surrounded by acid residue chains. No use of the polyol esters in this literature site has been mentioned.

The rate of diffusion of pharmacologically active agents from the ester and the rate of degradation of the ester as matrix material for active agents are too poor for practical use as implant or microcapsia.

03 Due to the hydrophobic properties of poly-s-hydroxycaproic acid residues, the esters are not suitable as matrix material for depot forms of pharmacologically active agents.

DK 173556 B1 2

Several forms of pharmacologically active agents have been proposed in the literature. EP Patent Application No. 92,918 discloses polypeptides in an ester matrix of, for example, polyvinyl alcohol (molecular weight 14,000) or polyethylene glycol (molecular weight 6,000 or 20,000) containing polymeric hydroxycarboxylic ester residues, e.g. from lactic acid 5 (molecular weight 26,000-114,000) and sometimes also glycol acid 10,000).

However, matrix materials with large molecular proportions of such polyol radicals have far too hydrophilic properties and degrade too quickly under conditions of use.

10

Furthermore, the strong hydrophilic properties and softness of these matrix materials impede the production thereof, the further processing and use of deposit forms, especially microcapsules.

Furthermore, as esters, for example, dextran is mentioned as a polyol, but due to the high molecular weight of dextran such an ester formation is practically impossible.

Deposits of pharmacologically active agents in a matrix of a polymer of polyols and hydroxycarboxylic acids are proposed as part of a very broad class of products in International Patent Application WO 78/00011. However, no examples of polymers of polyols and hydroxymonocarboxylic acids have been provided. Examples of depot forms of polyol esters containing polymeric dicarboxylic acid residues, e.g., of tartaric acid, are provided.

These polyol esters have a structure different from the products described above. They have a linear chain and alternatively contain polyol residues and dicarboxylic acid residues.

The esters formed have such a solubility that soluble precondensates must be formed to incorporate the pharmacologically active agents. Only then can the precondensed active agent containing ou matrix materials be further condensed.

35 DK 173556 B1 3

If saturated dicarboxylic acids are used, eg tartaric acid, it is indicated that the final total condensation must be carried out at elevated temperature (about 170-200 ° C), which is not suitable for heat sensitive active agents.

5

Using pentaerythritol as polyol, highly crosslinked products are formed which are not suitable for incorporation of pharmacologically active agents and which do not degrade sufficiently rapidly in vivo.

10

The mass decomposition rate of depot preparations made from these materials is too slow.

The manufacturing process described for the preparation of the microcapsules - 5 or other storage forms is similarly cumbersome.

The known matrix polymers generally have a disadvantageously short or long degradation time under conditions of use, for example in the body, in comparison with the required release time of the pharmacologically active agent, which causes the active agents to either disappear by 20, rapidly together with the matrix material or disappear completely. from the polymer matrix still present. Therefore, no further dose of the depot form can be administered later, since undesirable accumulation of polymeric matrix material may occur.

The object of the present invention is to overcome the above-mentioned drawbacks and to provide a useful pharmaceutical depot form for clinical use.

Further, depot forms prepared from the polyofester of the present invention have the advantage of having a drug release time which is satisfactorily long, e.g., 1 month, and then a short degradation period for the pulp. They can be used to incorporate a wide variety of e.g. water-soluble or hydrophobic active agents.

35 4 DK 173556 B1

In addition, the polyol esters of the present invention can be easily handled and readily processed for incorporation of the active agents and for the preparation of pharmaceutical formulations, e.g., microcapsules and implants. These microcapsules are not soft; they are therefore easy to administer through an injection needle.

The present invention relates to an ester of a polyol, said polyol containing at least 3 hydroxy groups and having a molecular weight of up to 20,000, wherein at least one hydroxy group in the polyol is in the form of an ester, with a poly or co-poly lactic acid residue, each of which has a molecular weight of at least 5000, for example from 5000 to, for example, 85,000. Another aspect of the present invention relates to a reaction product of a polyol containing at least 3 hydroxy groups and having a molecular weight of up to 20,000 or a reactive derivative thereof and lactic acid or a reactive derivative and, if desired, at least one additional hydroxycarboxylic acid or functional derivative thereof, having a polymer chain having a molecular weight of at least 5000. These products are referred to as "polyol esters of the invention".

In particular, the 20 P lyol residues are of a polyol containing a chain of carbon atoms. A particular polyol form is one which has linear structure and contains 3-6, especially 6, hydroxy groups. Suitable linear structure polyols include, for example, mannitol, pentaerythritol, sorbitol, ribito! and xylitol. Other preferred polyol forms are cyclic structure forms containing 4-30 hydroxy groups.

25

In particular, the cyclic structure polyols contain one or more saccharide units and have at least 3 hydroxy groups per unit. Examples of such polyols are polyols with fructose structure, for example fructose itself.

Particular cyclic structure polyols are those which have glucose structure, e.g., glucose itself, or which have 2-8 glucose units. These units are preferably connected in the 1.4 and / or 1.6 positions, especially in the 1.4 position. A polyol containing several glucose units linked in the 1.4 position is, for example, f5-cyclodextrin.

35 5 DK 173556 B1

The preferred polyol is glucose.

The polyol esters may have, for example, a polyol residue having at least 3 hydroxy groups in the form of esters containing polylactide or copolylactide chains. Thus, their structure may be branched, i.e. be star-shaped. Preferably, any such chain has identical hydroxycarboxylic acid residues.

The chains may contain lactide residues alone. Alternatively, they may contain further, for example, 1, 2, 3 or more specific hydroxycarboxylic acid residues, for example up to 70 mole percent, for example 30-70 mole percent.

Preferred auxiliary residues are glycolic acid residues. Preferably, up to 70 mole percent, e.g., 30-70 mole percent, especially 50 mole percent, of glycolic acid units are present. Instead of or in addition to the glycolic acid moieties, there may be other various moieties, e.g., ε-hydroxycaproic acids, preferably up to 20 mole percent.

The lactic acid units may occur in optically pure form (D or L-lac time form) or as a mixture thereof, e.g., their racemic form (D, L-lac time form).

20

The present invention further relates to a process for the preparation of a product according to the invention, characterized in that a polyol having a molecular weight of up to 20,000 and having at least 3 hydroxy groups or a reactive derivative thereof is esterified with lactic acid or a reactive derivative thereof. and, if desired, with at least one additional hydroxycarboxylic acid or a functional derivative thereof.

The process is particularly characterized in that a polyol having a molecular weight of up to 20,000 and having at least 3 hydroxy groups is reacted with lactic acid or in addition with at least one additional hydroxycarboxylic acid in lactone or dimer cyclic ester form in the presence of a catalyst which allows ring-opening polymerization.

6 DK 173556 B1

The catalyst is preferably Sn-octoate.

For example, the reaction components are mixed with the catalyst and reacted at elevated temperature.

If a solvent, e.g. toluene, is present, the components may be reacted at the reflux temperature of the solvent. Without solvent, the reaction temperature can be higher if, for example, as polyol glucose is used, up to approx. 170 ° C and if β-cyclodextrin is used, up to 180 ° C. The reaction is preferably carried out in the absence of water.

The polyol ester formed according to the invention can be purified and isolated in the usual manner.

The molecular weight of the purified product can be determined using conventional methods, preferably by gel permeation chromatography (GPC) using polystyrene as standard 15 (Mw), Dupont Ultrastyragel® 500 Å and 10,0000 Λ as column and tetrahydrofuran as solvent. , at room temperature.

The molecular weight (Mw) of the polyol esters of the invention is preferably between 20,000 and 200,000, for example between 20,000 and 80,000.

The molecular weight of the polyol esters of the invention depends on the weight ratio of the components of the reaction and the reaction conditions, e.g., the reaction temperature (cf. Example 8). Lower reaction temperature can lead to shorter polymer chains and thus to lower molecular weight polyol esters.

The insulation and purification may affect the molecular weight of the purified polyol ester. Changing the isolation and purification conditions leads to a change in molecular weight (cf. example 2). In general, since the polyol ester may appear as a mixture of molecules of different length chains, the composition of this mixture may be influenced by insulation and purification methods, for example, extraction, filtration and the isolation and purification fluids, and the amount thereof and the isolation and purification temperature.

7 DK 173556 B1

The molecular weight of the purified polymer can be increased by removing low molecular weight compounds, for example, by suitable precipitation of the polymer, for example in methanol, or by membrane filtration.

The amount of low molecular weight components can be reduced by membrane filtration to such an extent that their peaks in the molecular weight spectrum determined by GPC together have a height of up to 10%, preferably up to 7%, of the height of the polymer's Mw peak.

The invention thus also relates to a product in which the individual low molecular weight peaks according to GPC together constitute up to 10% of the height of the polyester Mw peak.

The polyol esters of the invention are particularly well suited for incorporating active agents and provide prolonged release effect of the active agents in the body.

The balance between hydrophobic and hydrophilic factors - the polyol residue represents the hydrophilic factor and the polylactide or co-polylactide residue the hydrophobic factor - can be regulated by changing the polyols, the degree of esterification of the hydroxy groups, the length and identity of the polymer chains, and the relative amounts of the hydroxycarboxylic acid units in the chain.

The polyol esters of the invention are therefore particularly suitable for the preparation of pharmaceutical depot preparations containing pharmacologically active agents. Such depot preparations may appear as a polyol ester matrix containing the active agent. Preferred depot forms are implants (e.g., for subcutaneous administration) and microcapsules (e.g., for oral or especially for parenteral, e.g., intramuscular, administration).

The invention therefore also relates to a pharmaceutical depot form having a matrix of the ester of the invention and containing a pharmacologically active agent.

The deposit forms are novel and constitute an aspect of the present invention.

8 DK 173556 B1

The depot forms can be prepared in the usual manner, the polyol esters of the invention being readily handled and often having a high concentration of the active agent incorporated.

For the preparation of microcapsules, the active agent can be dissolved in a volatile solvent, for example methylene chloride. A solution of the polyol ester, for example in the same solvent, can then be added and the resulting mixture can be injected into air while the temperature is carefully controlled and then dried to form microcapsules.

Alternatively, the active agent may be dissolved or suspended, e.g., in methylene dichloride, and the polyol ester may be dissolved in a volatile, water-immiscible solvent, e.g., methylene dichloride, after which the organic phase may be thoroughly mixed with a stirred aqueous solution, e.g., buffered to pH 7 , and optionally containing, for example, gelatin as an emulsifier. The organic solvent can then be removed from the resulting emulsion and the resulting microcapsules filtered off or separated by centrifugation, washed, for example, in a buffer, and dried.

For preparing implants, the active agent can be mixed with the polyol ester and dissolved in a volatile solvent, the solvent can be evaporated and the residue ground. An extrusion preparation may be formed in the usual manner, which is then pressed, for example into implant tablets of 5-15, especially 7 mm, and with 20-80 mg, e.g. 20-25 mg, matrix material at 75 ° C and 80 bar for 10 minutes. -20 minutes.

25 Depending on the active agent, the microcapsules can absorb on average up to 60% by weight of the active agent. The implants are preferably manufactured in such a way that they contain up to 60, e.g., 1-20, weight percent of the active substance.

For the active agent bromocryptin, microcapsules 30 containing up to 25% by weight, especially up to 18% by weight, and implants containing up to 18% by weight, of the active agent may be prepared.

9 DK 173556 B1

The microcapsules can have a diameter of from some submicron to a few millimeters. For pharmaceutical microcapsules, a diameter of no more than approx. 250 microns, eg 10-60 microns, to facilitate passage through an injection needle.

The depot preparation of the present invention can be used to administer a wide variety of classes of active agents, e.g., pharmacologically active agents such as contraceptives, sedatives, steroids, sulfonamides, vaccines, vitamins, antimigraine drugs, enzymes, bronchodilators, cardiovascular drugs, analgesics, antibiotics. tika, antigens, anticonvulsant drugs, anti-inflammatory drugs, anti-Parkinson's drugs, prolactin secretion inhibitors, antiastema drugs, geriatrics and antimalarials.

The depot preparations may be used for the known indications of the incorporated active agent concerned.

The exact amounts of active agent and depot preparation to be administered depend on a number of factors, for example, the disorder to be treated, the desired duration of treatment, the rate of release of the active agent and the degradability of the polymer matrix.

The desired compositions may be prepared in known manner. The amount of pharmacologically active agent needed and its rate of release may be determined on the basis of known in vitro or in vivo techniques described, for example, in Examples 26-29, e.g., how long the blood plasma concentration of a particular active agent is remains at an acceptable level. The degradability of the matrix can also be determined by in vitro or especially in vivo techniques, for example where the amount of matrix materials in a muscle is weighed after certain periods of time.

The depot compositions of the invention may be administered in the form of, for example, microcapsules, for example, orally, preferably subcutaneously or intramuscularly, preferably in the form of or in a suspension in a suitable liquid carrier or in the form of implants, for example, subcutaneously.

10 DK 173556 B1

Repeated administration of the depot compositions of the invention can be made when the polyol ester matrix has been sufficiently degraded, for example, after 1 month.

Examples of doses of preferred compounds are: 5 For prolactin secretion inhibition with bromocryptin, for example, an intramuscular depot preparation may be prepared which releases 2.5-7.5 mg of bromocryptin daily for approx. 30 days and, for example, contain 70-230 mg of bromocryp tin-mesyphate.

For example, for the treatment of bronchial asthma with ketotifen, an intramuscular depot preparation may be prepared which releases 0.5-0.8 mg of ketotifen daily for approx. 30 days and for example contains 15-25 mg of ketotifen.

For example, to reactivate cerebral metabolism with codergocrine, an intramuscular depot preparation may be prepared which releases 0.1-0.4 mg of codergocrine daily for approx. 30 days and contains approx. 3-12 mg.

Deposits for other active agents may be formulated in an analogous manner, e.g., to provide the known appropriate, e.g., therapeutic, concentration of active agent for parenteral use for a prolonged period of time, e.g., 30 days.

As noted above, polymer degradation can be monitored in experiments in vivo 20 and in vitro as described in Examples 24 and 25. It can be seen that the polyol esters of the invention degrade more rapidly than corresponding known polylactide and polylactide / glycolide acids, and more particularly degradation can be observed. in the early stage, for example up to 30 days, especially in the case of polylactide / glycolide polymer chains.

Membrane filtration results in residual polymer products, which generally have at the early stage, especially up to 30 days, less mass degradation rate than the rate of the corresponding unfiltered product. In the case of residual polyol esters of the invention, the degradation can be above 50% for up to 30 days, and in the case described in Example 6, approx. 70%. After 40-50 days the degradation can be practically complete.

In release rate tests in vitro and in vivo, the polyol esters of the invention can release the active agent at a rate which is of the same order as that of similar known polymeric poly or copolylactides, for example over 30 days.

5

The active agents can be released mainly by diffusion from the matrix and only to a small extent by degradation of the matrix material.

This results in a more regular release rate for the active agent.

10

An advantage of the polyester matrices of the invention is that, after practically complete release of active agent, they can rapidly degrade to an acceptable size which can be transported away from the site of administration by the body fluids.

15

According to the present invention there is provided a parenteral pharmaceutical depot composition for use as implant or microcapsules containing a pharmacologically active agent embedded or encapsulated in a polymer matrix of an ester of a polyol according to claim 1, which composition is formed to release all or substantially all active agent] for a prolonged period of time and the polymer is formed such that it degrades sufficiently rapidly to be transported away from the site of administration within 20 days of release of all or substantially all of the active agent.

The invention is further illustrated in the examples below, in which all temperature indications are uncorrected. HYFIO® is a known filter aid.

12 DK 173556 B1

Polyolester from D (+) -glucose, DL-dilactide and digfycolide Example 1 79.4 g (0.684 mol) diglycolide, 120.6 g (0.838 mol) DL-dilactide and 0.4 g (2.2 mlHimol) D (+) -glucose (0.2%) is placed in a 1.5 liter flask and heated to 135 ° C with stirring in argon atmosphere, after which 1 ml of Sn-octoate is added.

The reaction is exothermic. The temperature rises ten! 172 ° C. After 5 minutes, stirring is stopped and the brown viscous mixture is continued at 130-140 ° C for 17 hours. After cooling, add 500 ml of methylene dichloride. The mixture is dissolved as much as possible by boiling and the solvent is separated. This procedure is repeated and the residue is further extracted with 500 ml of methylene dichloride. The combined dark brown solutions (a total of 1500 ml) are purified with 50 g of HYFLO®, concentrated to 500 ml and treated with 500 ml of 10% aqueous HCl solution to remove the catalyst. The solution is washed five times with 500 ml of water to pH 4.5 and diluted to 1 liter with methylene dichloride.

The solution is treated with MgSO4 and with HYFLO®, concentrated to 500 ml and dipped over 3 hours to 3 liters of methanol at -60 ° C.

At this temperature, the mixture is stirred for 3 hours. The product is then filtered off and dried at 40 ° C in vacuo.

The molecular weight is determined by gel permeation chromatography (GPC):

Mw = 34,800, Mn = 19,600, Mw / Mn = 1.77.

Acid number: 6.8.

25 Unreacted lactide: 1.7%.

Unreacted glycolide: <0.4%.

Mole ratio glycolide / lactide in the polymer chains: 45/55.

NMR Spectrum (CDCl3), 360 MHz: 5.20 (m, 0.55H, -CH-lactic acid), 4.82 (m, 0.9H, -CH2-glycolic acid) and 1.58 (m , 3H, -CH2-lactic acid).

IR spectrum (CH, CU: v = 2950 (w, CH ~); 1760 (s, -COOR);

Jm £ ΓΠ3 X J

1390 and 1420 (w, CH 2); 1160 (s, -O-) and 1090 (s, -0-) cm \ EXAMPLES 2-5

By analogy with the example described in Example 1, the following 5 polyesters are prepared:

Ex. 2 * 3 * 45

Polyol 4 mg C ^ - 3.85 mg D (+) - 0.2 g D (+) - 0.2 g D (+) - 10 D (+) - glucose glucose + 0.15 glucose glucose (0, 2%) mg D (+) -1C14- (0.2%) (0.2%) glucose DL-Di-1.2 g 1.2 g 60.3 g 60.3 g lactide

Diglycolide 0.8 g 0.8 g 39.7 g 39.7 g

Sn-Octoat 10 vi 10 µl 0.5 ml 0.5 ml 20

Reaction - - - 168 ° C 155 ° C

temp.

VAT 31,400 26,400 34,600 23,600 25 _

Mn 17,300 10,600 20,700 13,300 14 DK 173556 B1

Ex. 2 * 3 * 45

Mw / Mn 1.81 2.50 1.67 1.77 5___

Molphoroid lactide / glycolide - - 55/45 58/42

Acid number - - 5.7 8.0 10___ In non-reacted lactide and - - 0.6% <0.4% glycol id - - <0.4% <0.2% 15 * For analysis results, cf. below.

Example 2:

The substance was prepared to show by analysis that the glucose was incorporated into the polymer and that a polyol ester was really formed.

Measurements were taken to intensify the NMR signal for the glucose.

13 13

The glucose was a pure C-labeled glucose with 98.3 atomic percent C

(LOT No. 2358-4 MSD ISOTOPES, Merck, Canada).

The 13 NMR signal for the C-glucose starting material was compared with the 13 signal for the C-glucose ester: C-Glucose-3 93.32 (d, C-1a); 77.63 (t, C-5P); 76.92 (t, C-3 &); 75.57 (t, C-28); 73.84 (t, C-3a); 72.92 (t, C-20); 72.24 (t, C-50); 71.07 (t, C-4a); 70.63 (t, C-4P); 61.95 δ (dxd, 0-6αβ).

13 C-The glucose ester of Example 2: 13 C-NMR Spectrum: (ppm) = 91.80 (m, C-Ίβ); 89.84 (m, C-1a); 72.51-66.73 (m, C-2,3,4,5a, β); 62.90 (m, C-6).

Since the glucose signals are all broad multiples, it is believed that the glucose was practically fully incorporated.

The lactide / glycolide / glucose molar ratio = 32.3 / 66.7 / 0.2.

Example 3: G PC Determination with simultaneous UV and radioactivity determination was used for analysis of these products. It is observed that the radioactivity in the test sample is proportionally distributed over the entire molecular weight range and that both the retention times in the UV and radioactivity determinations are equal.

The radioactivity in the test sample is approx. 30% of the predicted value, which shows that approx. 0.06% of the glucose was incorporated (from the beginning it was 0.2%).

EXAMPLE 6

The product of Example 4 was dissolved in methylene dichloride and purified by membrane filtration under a pressure of 2 atmospheres.

16 DK 173556 B1

Amiconappa ratu r.

Diaphragm: DDS 6000 mwco.

Type FS 81 PP.

Flow rate: 2.2 m / min.

Final volume: 2000 ml.

Residue: From NMR:

Mw = 42,200 Mw / Mn = 1.35 lactide / glycolide = 53/47 (molar ratio)

Mn = 31,300 Oxygen Number: 3.4

Unreacted lactide <0.2%

Unreacted glycolide <0.4%

Filtrate: From NMR: 15 Mw = 21,600 Mw / Mn = 1.58 lactide / glycolide = 53/46 Cmol ratio)

Mn = 13,600

Acid: 10.1

Unreacted lactide <1.2%

Unreacted Glycolide <0.4% EXAMPLE 7 39.7 g (0.342 mole) of diglycolide, 60.3 g (0.419 mole) of diactide, 0.2 g (1.1 millimole) of D (*) - glucose (0 , 2%) and 40 m! toluene is heated to boiling temperature (108 ° C) in a 750 ml flask with stirring, then 0.5 ml Sn-octoate is added. The reaction is slightly exothermic. The temperature rises to 112 ° C. After 3 hours, stirring is stopped and the brown viscous mixture is continued for 3 days at 110 ° C. After cooling, 500 ml of methylene dichloride is added and the mixture is diluted at boiling temperature, purified with HYFLO® and filtered.

The solution is evaporated to dryness and the residue is dissolved in methylene dichloride and shaken with 400 ml of 5% aqueous HCl solution. The solution is washed four times with 400 ml of water to pH 5 and diluted to 1 liter with methylene dichloride.

The solution is dried with MgSO4 and evaporated to dryness in vacuo at 40 ° C. The residue is dried in vacuo at 40 ° C.

Molecular weight: Mw = 32,200; Mn = 18,400; Mw / Mn = 1.75.

NMR and IR spectrum: As in Example 1.

EXAMPLE 8 Analogously to that described in Example 7, the following polyol ester is prepared in 345 ml of toluene.

Polyol: 0.6 g D (+) - glucose (0.2%) DL-Dilactide: 180.9 g

Diglycolide: 119.1 g Sn-Octoate: 1.5 ml

reaction

temp: 114.1 ° C

MW: 20,000

Mn: 12,000 25 Mw / Mn: 1.66

Mole ratio of lactide / glycolide:

Acid number: 7.2

Non-reacted: 30 lactide and <0.1% glycolide <0.4% 18 EXAMPLE 9

Analogous to that described in Example 6, the following product is prepared by membrane filtration from the product of Example 8: Flow rate: 1 ml / minute.

Final volume: 2200 ml

Residue: From NMR:

Mw = 26,200 Mw / Mn = 1.45 lactide / glycolide = 62/37 (molar ratio) 10 Mn = 18,000

Acid number: 4.0

Unreacted lactide <0.2%

Unreacted glycolide <0.4% Filtrate: From NMR:

Mw = 12,200 Mw / Mn = 3.75 lactide / glycolide = 60/40 (molar ratio)

Mn = 3,300

Acid number: 9.7

Unreacted lactide <0.2% 20 Unreacted glycolide <0.4% 19 DK 173556 B1

Polyolester from β-cyclodextrin, DL-dilactide and diglycolide EXAMPLE 10 26.1 g of diglycolide, 39.6 g of DL-dilactide and 0.635 g of β-cyclodextrin are heated to 140 ° C in a flask with stirring in a nitrogen atom, after which 0.125 ml of Sn-octoate is added. The reaction is markedly exothermic. The temperature rises to 180 ° C. After 10 minutes, stirring is stopped and the brown viscous mixture is continued at 140 ° C for 17 hours.

The purification and isolation is performed in an analogous manner as described in Example 1.

Molecular Weight (GPC): Mw = 75,700; Mn = 72,300; Mw / Mn = 1.05.

Unreacted lactide: 2%. Non-reacted glycolide: <0.4%.

Mole ratio glycolide / lactide in the polymer chains: 47/53.

NMR and IR spectrum: As in Example 1.

EXAMPLE 11

Analogous to that described in Example 3, the following polyol esters are prepared:

Polyol: 0.63 g of β-cyclodextrin.

DL-Dilactide: 39.6 g.

Diglycolide: 26.1 g.

Sn-Octoat: 0.13 ml.

Reaction temperature: 165.8 ° C.

Mw: 16,200; Mn: 5,100.

Mw / Mn: 3.18.

Mole ratio of lactide / glycolide: 54/46.

Acid number: 1.7.

Unreacted lactide: <0.2%. Non-reacted glycolide: <0.4%.

EXAMPLE 12

Analogous to that described in Example 3, the following polyol esters are prepared:

Polyol: 0.63 g of β-cyclodextrin dried at 120 ° C in vacuo.

DL-Dilactide: 39.6 g.

Diglycolide: 26.1 g.

Sn-Octoat: 0.13 ml.

Reaction temperature: 163.9 ° C.

Mw: 24,100; Mn: 10,700.

10 Mw / Mn: 2.26.

Mole ratio of lactide / glycolide: 53/47.

Oxygen number: 6.2.

Unreacted lactide: <0.2%.

Unreacted glycolide: <0.4%.

EXAMPLE 13

The product of Example 10 is treated analogously to that of Example 6. However, the filtration pressure is increased to 3 atmospheres.

Flow rate: 0.2 ml / minute.

20 _____

Residue: From nmR:

Mw = 72,200 Mw / Mn = 1.20 lactide / glycolide = 53/47 (molar ratio)

Mn = 59,800

Acid Number: 1.0 25__ 21 DK 173556 B1

Filtrate: From NMR:

Mw = 27,100 Mw / Mn = 1.75 lactide / glycolide = 52/48 (molar ratio)

Mn = 15,500

Oxygen Number: 21.2 EXAMPLE 14

The product of Example 10 is treated analogously to that of Example 6. However, the filtration pressure is increased to 2 atmospheres.

Flow rate: 0.3 ml / minute.

Residue:

Mw = 76,700 Mw / Mn = 1.06

Mn = 72,300 15 ..._

filtrate:

Mw = 67,900 Mw / Mn = 1.43

Mn = 47,600 EXAMPLE 15

Equal amounts of the residues of Examples 13 and 14, after intermediate solution in methylene dichloride, resulted in a mixture of the following composition: 22 DK 173556 B1

Mw = 70,000 Mw / Mn = 1.36

Mn = 51,600 EXAMPLES 16-17

Polyolester from D - (-) - mannitol, DL-dilactide and digiycolide 5 By analogy to the procedure described in Example 1, the following polyol esters were prepared:

Ex. 16 17 * 10 Polyol 0.1 g D (-) - mannitol (0.2%) 5.0 g D (-) - mannitol (10%) DL-Dilactide 30.15 g 30.15 g

Digiycolid 19.85 g 19.85 g 15__

Sn-Octoat 0.25 ml 0.25 ml

Reak.temp. 177.5 ° C 176.5 ° C

20 Mw 23,500 3,500

Mn 13,200 3,000

Mw / Mn 1.78 1.13 _

Mole ratio of lactide / glycolide 54:46 54:46

Acid number 6.2 1.4 30 _ 23 DK 173556 B1

Ex. 16 17 * In non-reacted 5 lactide and <0.1% <0.2% glycolide <0.4% <0.4% * For analytical purposes, cf. below.

EXAMPLES 18-23 10 Polyolester from polyols, DL-dilactide and diglycolide

By the procedure described in Example 1, the following polyol esters were prepared:

Ex. 18 19 * 20 21 22 23 15

Polyol 0.5 g 5 g 0.1 g 0.1 g 0.1 g 0.1 g penta-penta-sorbibrixyxy-D (-) - erythritol erythritol tol tol tol fructose (1%) (10) %) (0.2%) (0.2%) (0.2%) (0.2%) 20-DL-Di-30.15 g 30.15 g 30.15 g 30.15 g 30, 15 g 30.15 g lactide

Digly 19.85 g 19.85 g 19.85 g 19.85 g 19.85 g 19.85 g 25 colid

Sn-Oc 0.25 ml 0.25 ml 0.25 ml 0.25 ml 0.25 ml 0.25 ml toat

React 132.5 ° C 154.5 ° C 179.1 ° C 159.7 ° C 156.6 ° C 175 ° C

temp.

VAT 14,800 2,740 35,600 16,080 15,600 21,900 24 DK 173556 B1

Ex. 18 19 * 20 21 22 23

Mn 10,000 2,450 20,500 6,800 6,000 12,700 5_____

Mw / Mn 1.49 1.12 1.74 2.38 2.60 1.73

Mole ratio of lactide / - 10 glycolide 54:46 57:43 54:46

Acid number 7.5 0.73 In non-reacted 15 lactide and 0.4% <0.1% <0.1% glycolide 0.1% <0.4% <0.4% * For analysis purposes, cf. below.

Example 17: 20 NMR Spectrum (CDCl3) δ (ppm) = 5.23 (m, -CH- in lactic acid, 1H); 4.83 (m, -Cf- - glycolic acid, 1.73H); 4.46-4.17 (m, -CH- and -CHi mannitol and in the terminal lactic or glycolic acid units)

Mole ratio: lactide / glycolide / mannitol = 1 / 0.86 / 0.08.

This corresponds to an Mw of 1530 (however, the signal 4.46-4.17 also includes the terminal lactic or glycolic acid units).

Amount of mannitol used 672 x 10 6 mol%; incorporated amount 526 x 10 4 mol%.

For Example 19: 25 NMR Spectrum (CDCl 3) δ (ppm) = 5.23 (m, -CH- in lactic acid, 1H); 4.9-4.65 (m, -CH2 + in glycolic acid, 1.5H); 4.45-4.10 (m, -CH2 * in pentaerythritol and -CH- and -CHrf in the terminal lactic or glycolic acid units, 1H); 1.58 δ (m, CH 2 in lactic acid, 3H).

Mole ratio: lactide / glycolide / pentaerythritol: 1 / 0.75 / 0.15 (however, the signal 4.45-4.10 also includes the terminal lactic acid or glycolic acid units).

Quantity of pentaerythritol used is 960 x 10 6 mol%, incorporated amount (according to NMR) = 1000 x 10 6 mol% (the signals at 4.45-4.10 are not exclusively related to pentaerythritol).

Determination of the Degradation of Polyolester In vitro EXAMPLE 24 30-80 µm thick films are cast from 5% solutions of the polyofester of Example 6 in methylene dichloride. The films are dried for 50 hours at 40 ° C in vacuo and then for several days in a desiccator containing P 2 O 2.

300 mg of the film divided into small pieces was added to 30 ml of distilled water and shaken at 37 ° C (50 rpm).

The amount of polymer was determined periodically by filtration and weighing.

EXAMPLE 25

Implants in the form of tablets having a diameter of 7 mm and weighing 23-25 mg, pressed by a polyol ester granulate of Example 6 at 80 bar and 75 ° C for 10 minutes, were implanted intraperitoneally in rats. After a certain time, they were extracted from the tissue with methylene dichloride and thereby separated from the organic tissue material, evaporated to dryness and weighed.

26 DK 173556 B1

Release of active agents from polyol ester matrices in vitro Example 26

Release tests were performed with microcapsules containing bromo-cryptin as active agent. The microcapsules were prepared by the spray drying method described above with the following parameters:

Bromocryptin mesyfat 2.6 g

Matrix polymer of Example 9 (residue) 10.0 g

Methylene dichloride 100 ml

Spray conditions (NI RO equipment):

Inlet temperature 50 ° C

Initial temperature 40 ° C

Air pressure 2 atmospheres

Flow rate 32 ml / minute.

After preparation, the microcapsules were dried for 48 hours at 30 ° C in low vacuum, sieved (<180 µm) and washed with citrate buffer of pH 3. The microcapsules contained 17.9% of the active agent.

After repeated drying in low vacuum (48 hours, 35 ° C, 0.1 bar) and sieving (<180 µm), the microcapsules were gamma sterilized at 2.5 Mrad.

The release was measured photometrically at 301 nm at 25 ° C with citrate buffer, pH 4, as extraction medium, and poured freshly through the microcapsules at a flow rate of 2.5 ml / minute.

Within 24 hours, approx. 62% of the active agent regularly.

25 NB The in vitro release was measured at pH 4 due to the better solubility of bromocryptine at this pH.

EXAMPLE 27 27 DK 173556 B1

Release tests were performed with microcapsules containing coder-gocrin as active agent.

The microcapsules were prepared by the above-described emulsion process with the following parameters:

Codergocrin Base 7 g

Matrix polymer of Example 5 13 g

Methylene dichloride 40 ml

Ethanol 94% 30 ml Emulsification conditions:

Volume ratio of organic phase to aqueous phase: 1:65 Speed of rotation of the stirrer: p = 3100 rpm.

The release was measured as described in Example 26.

EXAMPLE 28 The procedure described in Example 27 was carried out with the following parameters:

Ketotifen Base 5 g

Matrix polymer of Example 5 15 g

Methylene dichloride 80 ml Emulsification conditions:

Volume ratio between organic phase and aqueous phase: 3: 130 p = 2000 rpm.

Stirring time: 2 hours

The microcapsules contained 16.5% ketotifen.

EXAMPLE 29

Release of active agents from polyol ester matrices in vivo

Microcapsule release capsules containing bromocryptin as active agent were performed.

The microcapsules were prepared by the above-described spray drying process in a NI RO spray drying apparatus provided with centrifugal spray nozzle. The matrix polymer consisted of the product of Example 4 and contained 17.8¾ bromocryptin.

A portion of these microcapsules, corresponding to 5.0 mg of bromocryptine mesylate, in a carrier of 0.2 ml of sodium carboxymethyl cellulose was injected into the right thigh muscle of a rabbit. Blood samples were taken periodically from the rabbit for 21 days.

The blood level of the drug was measured by a specific radioimmunoassay and had a mean value of 1.6 ng / ml (A.U.C. = 33.0). The blood-15 levels were practically all between 1.20 and 1.80 ng / ml.

Claims (9)

An ester of a polyol, said polyol containing at least three hydroxy groups and having a molecular weight of up to 20,000, wherein at least one hydroxy group of said polyol is in the form of an ester, with a poly or co-poly lactic acid residue each having a molecular weight of at least 5000. A reaction product between a polyol containing at least 3 hydroxy groups and having a molecular weight of up to 20,000 or a reactive derivative thereof and lactic acid or a reactive derivative thereof and, if desired, at least one additional hydroxycarboxylic acid or functional derivative thereof, which product has a polymer chain having a molecular weight of at least 5000. Product according to claim 1, characterized in that the polyol is a polyol having a glucose structure. Product according to claim 1, characterized in that it contains acid residues comprising 30-70 mole percent glycolic acid units. Product according to claim 1, characterized in that any separate low molecular weight peak according to GPC constitutes a total of up to 10% of the height of the polyester MW peak. Process for the preparation of a product according to claim 1, characterized in that a polyol having a molecular weight of up to 20,000 and having at least 3 hydroxy groups or a reactive derivative thereof is esterified with lactic acid or a reactive derivative thereof and, if desired, with at least one additional hydroxycarboxylic acid or a functional derivative thereof. Depot matrix material of a product according to claim 1, characterized in that it contains a pharmacologically active compound. Depot matrix material of a product according to claim 7, characterized in that they contain bromocryptin, ketotifen or codergocrine as a pharmaceutically active agent. DK 173556 B1 A parenteral pharmaceutical depot composition for use as an implant or microcapsules containing a pharmacologically active agent embedded in or encapsulated in a polymer matrix of an ester of a polyol according to claim 1, which composition is formed to release all or substantially all of the active substance into a drug. prolonged period of time and the polymer is formed such that it degrades sufficiently rapidly to be transported away from the site of administration within 20 days of release of all or substantially all of the active agent. Composition according to claim 9, characterized in that it contains bromocryptine, ketotifen or codergocrine as a pharmaceutically active agent.